The goals of this project are to develop in the laboratory, using model systems and primary CLL cells in vitro an understanding of the mechanisms of action of anticancer agents acting alone and in mechanism-based combinations. This knowledge base will provide rationales for the design and evaluation of clinical trials that will test hypotheses regarding the actions and interactions of these agents in CLL cells in patients during therapy. Thus, the central hypothesis we will test is that knowledge derived from an understanding of the metabolism, mechanisms of action, and the interactions of new anticancer therapeutics can be used to design and evaluate novel therapeutic regimens for the treatment of patients with CLL. To achieve these goals, we will address the following questions: 1. Do nucleoside analogs with novel actions provide pharmacological and clinical advantages over fludarabine for the treatment of B-CLL? Our focus here will be on the new nucleoside analog, clofarabine which has pharmacologic properties different from fludarabine. 2. Can strategies to reduce survival proteins selectively kill CLL cells? We are developing 8-chloro-adenosine ribonucleotide analog that reduces cellular bioenergy and blocks transcription. Also, we will evaluate the transcription-directed actions of flavopiridol. The actions of each of these agents decreases anti-apoptotic proteins in CLL cells. 3. Will mechanism-based combinations of cytotoxic agents improve outcome in CLL patients? The cellular responses to inhibition of excision DNA repair processes will be investigated in CLL cells, and extended to new DNA damaging agents and drugs that inhibit DNA repair. 4. Can orsaponin, a synthetic natural compound with potent anticancer activity and unique mechanism of action, be used as a novel agent for treatment of CLL? The action mechanism(s) of this novel agent that selectively kills CLL cells independent of p53 status will be investigated in preparation for clinical development. Interactions with other projects in this program will strengthen our investigations.